Objective To explore the effect of Rehmannia glutinosa polysaccharide (RGP) on apoptosis of osteoarthritis (OA) chondrocytes induced by sodium iodoacetate (MIA) via the regulation of long-chain non-coding RNA (lncRNA) maternal expression gene 3 (MEG3). Methods Rat chondrocytes were cultured with MIA 0, 1, 2, 4, and 8 μmol/ L to induce chondrocyte injury, and were then treated with RGP 50, 100, 200, 400, and 800 mg/ mL, respectively, to detect the appropriate experimental concentration. Rats were divided into a normal group, MIA group, RGP group, RGP+control (NC) small interfering RNA (siRNA) group, and RGP+si-MEG3 group. Cell viability was detected by Cell Counting Kit-8 (CCK-8) assay and apoptosis was detected by Hoechst 33258 staining and flow cytometry. mRNA levels of MEG3, metalloproteinase 13 (MMP-13), type Ⅱ collagen-α1 (COL2A1), and proteoglycan (ACAN) were detected by real-time quantitative polymerase chain reaction. Protein levels of PI3K, phospho (p) PI3K, serine/ threonine kinase(AKT), p-AKT, BAX, BCL-2, and caspase3 were detected by Western blot. Results MIA decreased chondrocyte viability and induced apoptosis in a dose-dependent manner, decreased MEG3, COL2A1, and ACAN mRNA levels, and increased MMP-13 mRNA levels (P<0. 05). RGP 100, 200, 400, and 800 mg/ mL increased chondrocyte viability and MEG3 levels (P <0. 05). Cell viability, MEG3, COL2A1, and ACAN mRNA, and p-PI3K/ PI3K, p-AKT/ AKT, and BCL-2 protein levels were decreased in the MIA group compared with the control group, while the apoptosis rate, MMP-13 mRNA, and BAX and caspase3 protein levels were increased (P<0. 05). Cell viability, MEG3, COL2A1, and ACAN mRNA, and p-PI3K/ PI3K, P-AKT/ AKT, and BCL-2 protein levels were increased in the RGP group compared with the MIA group, while the apoptosis rate, MMP-13 mRNA, and BAX and caspase3 protein levels were decreased (P<0. 05). Knockdown of MEG3 weakened the protective effect of RGP on MIA-induced chondrocyte injury. Conclusions RGP can promote the synthesis of chondrocyte extracellular matrix and inhibit cell apoptosis and MIA-induced chondrocyte damage, possibly acting via a mechanism related to the up-regulation of MEG3 expression and induction of PI3K/ AKT pathway activation.